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Relationship: 1806


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Histone acetylation, increase leads to Altered, Gene Expression

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Histone deacetylase inhibition leads to neural tube defects adjacent Not Specified Not Specified Allie Always (send email) Under Development: Contributions and Comments Welcome

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

The structure of chromatin is a major component of gene regulation in eukaryotes by providing or preventing accessibility for the transcriptional machinery to the relevant regulatory DNA sequences. Histone acetylation is one of the major posttranslational modifications that are involved in the regulation of gene expression. Generally spoken, acetylation is correlated with actively transcribed genes, whereas hypoacetylation is involved in gene silencing.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

In all eukaryotes, the DNA containing the genetic information of an organism is organized in chromatin. The basic unit of chromatin is the nucleosome around which the naked DNA is wrapped. A nucleosome consists of two copies of each of the core histones H2A, H2B, H3 and H4 (Luger et al., 1997). In general, chromatin is a permissive structure for all DNA-dependent processes such as DNA replication, recombination, repair, and transcription and therefore also for gene expression. However, chromatin structure is very dynamically regulated and can be made accessible for the transcriptional machinery and is, therefore, an important mechanism of gene regulation. One mechanism of chromatin structural regulation is the post-translational modifications of the histone proteins including the acetylation of lysine residues (reviewed in (Bannister and Kouzarides, 2011; Bannister et al., 2002; Kouzarides, 2007; Tessarz and Kouzarides, 2014)). These modifications serve as a docking station for further proteins and protein complexes that finally open or close the chromatin structure and allow or inhibit access of the transcriptional machinery (Musselman et al., 2012) or directly influence DNA histone interaction (reviewed in (Tessarz and Kouzarides, 2014). Histones get acetylated by histone acetyltransferases (HAT) and deacetylated by histone deacetylases (HDAC) (reviewed in (Gallinari et al., 2007; Bannister and Kouzarides, 2011; Kouzarides, 2007)). In general, it can be assumed, hyperacetylated histones are associated with actively transcribed genes, whereas hypoacetylation of histones is involved in gene silencing.

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

All above-mentioned analysis are indirect or in purified systems. Therefore a direct cause-consequence relation is difficult to obtain.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help


List of the literature that was cited for this KER description. More help

Balmer, N. V., Weng, M. K., Zimmer, B. et al. (2012). Epigenetic changes and disturbed neural development in a human embryonic stem cell-based model relating to the fetal valproate syndrome. Hum Mol Genet 21, 4104-4114. doi:10.1093/hmg/dds239

Balmer, N. V., Klima, S., Rempel, E. et al. (2014). From transient transcriptome responses to disturbed neurodevelopment: Role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol 88, 1451-1468. doi:10.1007/s00204-014-1279-6

Bannister, A. J., Schneider, R. and Kouzarides, T. (2002). Histone methylation: Dynamic or static? Cell 109, 801-806. doi:S0092867402007985 [pii]

Bannister, A. J. and Kouzarides, T. (2011). Regulation of chromatin by histone modifications. Cell Res 21, 381-395. doi:10.1038/cr.2011.22

Bernstein, B. E., Tong, J. K. and Schreiber, S. L. (2000). Genomewide studies of histone deacetylase function in yeast. Proc Natl Acad Sci U S A 97, 13708-13713. doi:10.1073/pnas.250477697

Foglietti, C., Filocamo, G., Cundari, E. et al. (2006). Dissecting the biological functions of drosophila histone deacetylases by rna interference and transcriptional profiling. J Biol Chem 281, 17968-17976. doi:10.1074/jbc.M511945200

Gallinari, P., Di Marco, S., Jones, P. et al. (2007). Hdacs, histone deacetylation and gene transcription: From molecular biology to cancer therapeutics. Cell Res 17, 195-211. doi:7310149 [pii]


Kouzarides, T. (2007). Chromatin modifications and their function. Cell 128, 693-705.

Musselman, C. A., Lalonde, M. E., Cote, J. et al. (2012). Perceiving the epigenetic landscape through histone readers. Nat Struct Mol Biol 19, 1218-1227. doi:10.1038/nsmb.2436

Robyr, D., Suka, Y., Xenarios, I. et al. (2002). Microarray deacetylation maps determine genome-wide functions for yeast histone deacetylases. Cell 109, 437-446.

Tessarz, P. and Kouzarides, T. (2014). Histone core modifications regulating nucleosome structure and dynamics. Nat Rev Mol Cell Biol 15, 703-708. doi:10.1038/nrm3890

Xu, F., Zhang, K. and Grunstein, M. (2005). Acetylation in histone h3 globular domain regulates gene expression in yeast. Cell 121, 375-385. doi:10.1016/j.cell.2005.03.011

Zupkovitz, G., Tischler, J., Posch, M. et al. (2006). Negative and positive regulation of gene expression by mouse histone deacetylase 1. Mol Cell Biol 26, 7913-7928. doi:10.1128/MCB.01220-06